Coronavirus -- HCQ, RCT, politics

This article, title Hydoxychloroquine: A Morality Tale, is sort of long (> 15,000 words), but well worth reading. It is about the drug (HCQ), randomized control trials (RCT), facing a pandemic due to a novel virus, and how they have been so politicized.

Remdesivir has been politicized, too, but not as much. Many people on the political left favor it. Its success in treating Covid is modest. Some had a change of heart when they assumed the FDA was unduly influenced by the Trump administration when the emergency use authorization was broadened for remdesivir. See my September 1 post.  

The article gets philosophical: "We live in a culture that has uncritically accepted that every domain of life is political, and that even things we think are not political are so, that all human enterprises are merely power struggles, that even the idea of “truth” is a fantasy, and really a matter of imposing one’s view on others. For a while, some held out hope that science remained an exception to this. That scientists would not bring their personal political biases into their science, and they would not be mobbed if what they said was unwelcome to one faction or another. But the sordid 2020 drama of hydroxychloroquine—which saw scientists routinely attacked for critically evaluating evidence and coming to politically inconvenient conclusions—has, for many, killed those hopes." 

Coronavirus - convalescent plasma

The FDA has granted emergency use authorization (EUA) to convalescent plasma to treat hospitalized patients with Covid-19 (link). This is plasma containing antibodies drawn from persons who had Covid-19 and have fully recovered.

A Wall Street Journal op-ed calls the FDA's decision good. The op-ed being behind a paywall, some reading this may only be able to see the start of it. Hence, the following in italics are some excerpts. 

This is what occurred with the anti-malaria drug hydroxychloroquine and now is happening with convalescent plasma, which the FDA on Sunday granted “emergency use authorization” (EUA). Mr. Trump was wrong to tweet over the weekend that “the deep state” at the FDA was thwarting development of therapies and vaccines to sabotage his re-election.

There’s no evidence for his claim or that the FDA is making decisions based on anything but the science. There is, however, ample evidence that convalescent plasma may be effective and that the potential benefits outweigh the risks. This is the FDA standard for EUAs, and the agency was right to increase patient access to the potentially life-saving therapy.

But individuals produce varying levels and types of antibodies in response to viruses, so convalescent plasma from some recovered patients will be more effective. This makes it especially hard to do randomized trials with control groups. The two randomized placebo trials on convalescent plasma were inconclusive.

The evidence for convalescent plasma relies on more than a dozen observational studies and clinical trials that don’t meet the randomized placebo standard. 

Current evidence suggests that benefit is most likely in patients treated early in the course of the disease (e.g., prior to intubation). This make sense. Hospitalized patients in the early stages of the disease tend to have low levels of lymphocytes that produce antibodies. Infusing them with more antibodies probably helps. But patients who must be intubated may be suffering from a cytokine inflammatory storm, which mere antibodies won’t calm.

They [others, e.g. The New York Times] want evidence from gold-standard clinical trials, but these are hard to pull off in a pandemic and often yield conflicting results.

Thousands typically need to be enrolled to prove statistically significant benefits, and trial designs obscure benefits among patient subsets. It’s unlikely that any treatment will show an aggregate benefit among all sick patients because people suffer different symptoms at different stages of the disease.

*****

Of course, and like the op-ed says, others have lambasted the decision, such as The New York Times. What else should one expect from that source? Again, the following in italics are excerpts.

F.D.A. ‘Grossly Misrepresented’ Blood Plasma Data, Scientists Say

But scientists were taken aback by the way the administration [President Trump, Azar of HHS, Hahn of FDA] framed this data, which appeared to have been calculated based on a small subgroup of hospitalized Covid-19 patients in a Mayo Clinic study: those who were under 80 years old, not on ventilators and received plasma known to contain high levels of virus-fighting antibodies within three days of diagnosis. 

The WSJ op-ed compared the plasma treatment to the treatments dexamethasone and  remdesivir. The two drugs are for more serious cases, but they haven't clearly passed a gold standard either. The New York Times article said nothing about those drugs and them versus the gold standard. It seems the gold standard is for things the NYT doesn't like, but not for things the NYT does like.

Update 8/26: FDA Commissioner Stephen Hahn issues mea culpa for his plasma treatment claims, saying he had overstated the benefits of convalescent plasma as a treatment of coronavirus at a news conference last weekend with President Trump (link).

Update 8/29: A key person behind Stephen Hahn's apology was removed (reassigned, not fired) from her public relations position (link).

Coronavirus – clinical trials #4

If an experiment or clinical trial were to show that a drug treatment could cure Covid-19 or block it from making the patient sicker, then Mill’s Method of Difference only identifies that the drug treatment works. A more complete causal explanation would include explaining why the drug treatment works. I have not seen any such explanation why regarding hydroxychloroquine (HCQ) or HCQ + zinc. Maybe somebody can explain why, but I can't. The only drug treatment I have read about that plausibly explains why it works is RLF-100, i.e. aviptadil (Coronavirus - drug news).

News

Yesterday Yahoo News reported that the FDA granted Investigational New Drug (IND) permission to test the use of RLF-100, i.e. aviptadil, for patients with moderate and severe Covid-19 in order to prevent progression to respiratory failure (Yahoo News). 

Also yesterday President Trump signed an executive order requiring U.S. government agencies to purchase “all essential medicines” from American sources (NBC News). The patent for RLF-100 is owned by a Swiss company. On the other hand, it is partnering with NeuroRx, a USA-Israel company, to produce and sell the drug in the USA. I won't try to predict how the executive order will affect RLF-100's future. 

Coronavirus – clinical trials #3

Yesterday’s post was about a clinical trial for a coronavirus vaccine and Mill’s Method of Difference. In this post I consider a clinical trial for a Covid-19 cure and Mill’s Method of Difference.

A clinical trial for a cure for Covid-19 would enroll patients who already have Covid-19. There is no contingency analogous to becoming infected like there is for a coronavirus vaccine clinical trial. On the other hand, there are a lot more variables – a variety of patients’ ages, each patient’s health status, degree of infection, and so forth. Dosage amounts may also differ, for which the logic is also Mill’s Method of Concomitant Variation.

Dr. Anthony Fauci often invokes the “gold standard” for clinical trials (randomized double blind placebo control studies) when he comments on any drug doctors might prescribe to treat patients. This standard is mainly for new drugs, but may also be used for already FDA approved medications for treating medical conditions outside the scope of prior approval, e.g. remdesivir for Covid-19. These are often called “off label” uses. It is also called repurposing. The FDA has relaxed its standards for drugs to treat Covid-19 patients. The FDA has made emergency use authorizations (EUA). The FDA may grant Investigational New Drug (IND) permission to test a drug. To my knowledge no drugs – even Remdesivir, which Fauci personally approves -- have passed the “gold standard” for treating Covid-19.

The following are the NIH guidelines for the treatment of Covid-19 with four different drug therapies.  Remdesivir.  Chloroquine and Hydroxychloroquine.  Hydroxychloroquine Plus Azithromycin.  Dexamethasone.

Conspicuously non-existent are web-pages for (1) Hydroxychloroquine (HCQ) Plus Zinc and (2) HCQ Plus Zinc Plus Azithromycin, especially with outpatients. Several doctors who recommend using HCQ for Covid-19, mainly with outpatients, have said zinc is a necessary enabler and without zinc the HCQ is minimally effective. Note that the NIH's web-page for HCQ + Azithromycin page concerns only trials with inpatients (hospitalized).

Dr. Anthony Fauci still approves using remdesivir. Regardless, it falls far short of a cure for Covid-19. Like the above web-page shows, some clinical trials have shown at best that remdesivir reduced  recovery time compared to a placebo. Other trials have shown no observed improvement or the data is insufficient. I would not call that passing the “gold standard.”

Dr. Fauci and the NIH recommend dexamethasone for some patients. The web-page above says clinical trials have shown significant mortality reduction in patients requiring supplemental oxygen, with or without a ventilator. On the other hand, no benefit of dexamethasone was observed in patients who did not require supplemental oxygen. Does this mean that dexamethasone passed the “gold standard”? Arguably 'yes' in some cases, but a cure? Many who got the drug still died during the trial.

Despite the many unknowns about the coronavirus and Covid-19 and the long time frame of clinical trials, Dr. Fauci often appeals to the “gold standard” as an argument against anything that doesn’t meet his or the FDA’s approval. In effect, he has little regard for individual judgments of practicing physicians to prescribe drugs absent his or the FDA’s approval, despite the lack of “gold standard” drugs for curing Covid-19 or halting its progress.

Dr. Fauci also consequently has shown little regard for giving placebos to patients who are seriously ill with Covid-19. Assume such patients participate in a clinical trial hoping to be cured and they later learn – if they survive – they were given a placebo and other patients in the trial who got the drug benefited. I suspect they would not be content.

Coronavirus - drug news

A Reuters article says: "Critically ill COVID-19 patients recovered rapidly from respiratory failure after three days of treatment with RLF-100, a therapy granted fast-track designation in the United States, two drug companies said on Sunday."

The drug plausibly blocks replication of the SARS-CoV-2 virus in human lung cells and monocytes (white blood cells).

  

The article also appeared in the New York Post and Jerusalem Post.

A Science Alert article says: "A paper came out in Nature on July 22 that further underscores earlier studies that show that neither the malaria drug hydroxychloroquine nor chloroquine prevents SARS-CoV-2 – the virus that causes COVID-19 – from replicating in lung cells."

Zinc was used with hydroxychloroquine in some cases, but the article doesn't mention zinc.

RLF-100 was used to treat critically ill patients, whereas earlier alleged successes with hydroxychloroquine were mainly with early-stage mildly infected patients or as prevention. The blocking versus not blocking replication of the virus is a big difference, too. 

Update August 4 

This page shows a transcript of Dr. Anthony Fauci testifying about hydroxychloroquine. He is acutely asked about using zinc with hydroxychloroquine, and he evades the question. (He refers to corticosteroids, which contain no zinc.) He clings to the "gold standard" despite its very long time frame and requiring giving very ill patients a placebo, and the urgency of finding a cure. 

Coronavirus -- drugs

Two doctors tell how government and the politically connected have interfered with doctors treating their patients for COVID-19.

https://anthraxvaccine.blogspot.com/2020/06/how-false-hydroxychloroquine-narrative.html

https://soundcloud.com/user-694711047/covid-19-and-patient-rights-guest-kris-held-md

Use of hydroxychloroquine and zinc to treat COVID-19 outpatients first made the news in March. Dr. Vladimir Zelenko of New York claimed successful treatment of 669 patients. Snopes declared the story "unproven" (link).  Note that Snopes does not say the treatment protocol is "disproven" nor give any proven treatment or better treatment. Snopes does say public health officials largely disagree with Dr. Zelenko's risk assessment of the treatment protocol. A French doctor, Didier Raoult, also made the news, reporting successful use of the same drugs.

Hydroxychloroquine Should Be Available Over The Counter  I believe the graph shown on the page is somewhat misleading since the age structure of each country's population is ignored. Countries with high CFRs (case fatality rates; red bars) often have high percents of older people, and countries with low CFRs (green bars) often have low percents of older people (link).

I am not a doctor or medical professional of any kind. Regardless, the politically powerless have a right of free speech as much as anybody else. The mainstream media ignores anybody -- such as these two doctors -- who doesn't fit its favored narrative. Also, the extent of interference by people in government and the politically connected is worthy of concern. They like to pose as knowing more and impose their authority on all, heavily supported by the mainstream media. In my opinion their performance during this pandemic has been poor. 

Other drug news

Study finds fenofibrate may downgrade Covid-19 to common cold level

British pharma firm claims small trial on a coronavirus treatment could signal ‘major breakthrough’

Update July 27

https://www.newsweek.com/key-defeating-covid-19-already-exists-we-need-start-using-it-opinion-1519535